Long-Term Observation of Patients With Cancer - an Entity-Independent Registry for Healthcare and Translational Research at the University Medicine Dresden (Cancer-Reg-VT). / Langzeitbeobachtung von Patienten mit Krebserkrankungen ­ ein entitätsunabhängiges Register für Versorgungsforschung und translationale Forschung an der Universitätsmedizin Dresden (Cancer-Reg-VT).

INTRODUCTION: Translational research is important, especially in medicine where decisions affect people's lives. Clinical registries and the studies embedded in them allow the depiction of actual care practice under routine conditions. Translating the findings of health services research back into clinical research through prospective cohort studies has the potential to drive medical innovations faster, more effectively and, above all, in a more targeted manner. These must therefore be a central component of cutting-edge oncological research. OBJECTIVE: The aim of the registry is the establishment of clinical cohorts and the provision of a comprehensive, high-quality data set for oncological diseases. METHODS/DESIGN: The registry will prospectively record all patients treated for cancer at Dresden University Hospital (UKD). In addition to the data from the hospital information systems (ORBIS, TDS, GEPADO, etc.), monitoring of health-related quality of life (HRQOL) is to be carried out at regular intervals at the beginning and during the course of treatment. In addition, individual linkage with data from clinical cancer registries and health insurance companies (including AOK PLUS) is planned for a period of five years before and after inclusion. All these data will be merged in a registry database. The selection of variables and measurement time points is closely based on the guidelines for colorectal carcinoma of the international initiative ICHOM (International Consortium for Health Outcomes Measurement). The study management software (STeVe) separates personal identification characteristics (IDAT) and medical data (MDAT) at an early stage. The independent trust centre of the TU Dresden (Treuhandstelle) ensures that no personal data enter the registry database. It is thereby also ensured that the data owners involved (UKD, biobank, health insurance company, cancer registry, patient) only receive the personal data they need for allocation. The MOSAIC software tools recommended by the TMF (Technologie- und Methodenplattform für die vernetzte medizinische Forschung e.V.) are used to manage the pseudonyms. DISCUSSION/CONCLUSION: With the registry, previously missing evidence on the effectiveness, safety and costs of diagnostic and therapeutic measures can be made, taking into account long-term and patient-reported outcomes of routine care. The data potentially allow for the identification of barriers to and facilitators of innovative promising cancer diagnostics and therapies. They also enable generation of scientifically relevant hypotheses in the field of translational and outcomes research.

Phase I pharmacokinetic/pharmacodynamic study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) in first-line treatment of patients with metastatic colorectal cancer.

PURPOSE: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC). METHODS: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3). Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted. RESULTS: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogen-activated protein kinase (MAPK) and induced p27 expression in the skin. CONCLUSION: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.